Carotid geometry is independently associated with complicated carotid artery plaques.

Introduction: Complicated carotid artery plaques (cCAPs) are associated with an increased risk of rupture and subsequent stroke. The geometry of the carotid bifurcation determines the distribution of local hemodynamics and could thus contribute to the development and composition of these plaques. Therefore, we studied the role of carotid bifurcation geometry in the presence of cCAPs. Methods: We investigated the association of individual vessel geometry with carotid artery plaque types in the Carotid Plaque Imaging in Acute Stroke (CAPIAS) study. After excluding arteries without plaque or with insufficient MRI quality, 354 carotid arteries from 182 patients were analyzed. Individual parameters of carotid geometry [i.e., internal carotid artery (ICA)/common carotid artery (CCA) ratio, bifurcation angle, and tortuosity) were derived from time-of-flight MR images. The lesion types of carotid artery plaques were determined according to the American Heart Association classification of lesions by multi-contrast 3T-MRI. The association between carotid geometry and a cCAP was studied using logistic regression after adjusting for age, sex, wall area, and cardiovascular risk factors. Results: Low ICA/CCA ratios (OR per SD increase 0.60 [95%CI: 0.42-0.85]; p = 0.004) and low bifurcation angles (OR 0.61 [95%CI: 0.42-0.90]; p = 0.012) were significantly associated with the presence of cCAPs after adjusting for age, sex, cardiovascular risk factors, and wall area. Tortuosity had no significant association with cCAPs. Only ICA/CCA ratio remained significant in a model containing all three geometric parameters (OR per SD increase 0.65 [95%CI: 0.45-0.94]; p = 0.023). Conclusions: A steep tapering of the ICA relative to the CCA and, to a lesser extent, a low angle of the carotid bifurcation were associated with the presence of cCAPs. Our findings highlight the contribution of bifurcation geometry to plaque vulnerability. Thus, assessment of carotid geometry could be helpful in identifying patients at risk of cCAPs.

Guideline "Transient Global Amnesia (TGA)" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie): S1-guideline.

INTRODUCTION: In 2022 the DGN (Deutsche Gesellschaft für Neurologie) published an updated Transient Global Amnesia (TGA) guideline. TGA is characterized by a sudden onset of retrograde and anterograde amnesia for a period of one to a maximum of 24 h (with an average of 6 to 8 h). The incidence is estimated between 3 and 8 per 100,000 population/year. TGA is a disorder that occurs predominantly between 50 and 70 years. RECOMMENDATIONS: The diagnosis of TGA should be made clinically. In case of an atypical clinical presentation or suspicion of a possible differential diagnosis, further diagnostics should be performed immediately. The detection of typical unilateral or bilateral punctate DWI/T2 lesions in the hippocampus (especially the CA1 region) in a proportion of patients proves TGA. The sensitivity of MRI is considered higher when performed between 24 and 72 h after onset. If additional DWI changes occur outside the hippocampus, a vascular etiology should be considered, and prompt sonographic and cardiac diagnostics should be performed EEG may help to differentiate TGA from rare amnestic epileptic attacks, especially in recurrent amnestic attacks. TGA in patients < 50 years of age is a rarity, therefore it is mandatory to rapidly search for other causes in particular in younger patients. The cause of TGA is still unknown. Numerous findings in recent years point to a multifactorial genesis. Because the pathomechanism of TGA is not yet clearly known, no evidence-based therapeutic or prophylactic recommendations can be made. CONCLUSIONS: There is no evidence for chronic sequelae of TGA with respect to cerebral ischemia, chronic memory impairment, or the onset of dementia-related syndromes.

RBD-Based ELISA and Luminex Predict Anti-SARS-CoV-2 Surrogate-Neutralizing Activity in Two Longitudinal Cohorts of German and Spanish Health Care Workers.

The ability of antibodies to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important correlate of protection. For routine evaluation of protection, however, a simple and cost-efficient anti-SARS-CoV-2 serological assay predictive of serum neutralizing activity is needed. We analyzed clinical epidemiological data and blood samples from two cohorts of health care workers in Barcelona and Munich to compare several immunological readouts for evaluating antibody levels that could be surrogates of neutralizing activity. We measured IgG levels against SARS-CoV-2 spike protein (S), its S2 subunit, the S1 receptor binding domain (RBD), and the full length and C terminus of nucleocapsid (N) protein by Luminex, and against RBD by enzyme-linked immunosorbent assay (ELISA), and assessed those as predictors of plasma surrogate-neutralizing activity measured by a flow cytometry assay. In addition, we determined the clinical and demographic factors affecting plasma surrogate-neutralizing capacity. Both cohorts showed a high positive correlation between IgG levels to S antigen, especially to RBD, and the levels of plasma surrogate-neutralizing activity, suggesting RBD IgG as a good correlate of plasma neutralizing activity. Symptomatic infection, with symptoms such as loss of taste, dyspnea, rigors, fever and fatigue, was positively associated with anti-RBD IgG positivity by ELISA and Luminex, and with plasma surrogate-neutralizing activity. Our serological assays allow for the prediction of serum neutralization activity without the cost, hazards, time, and expertise needed for surrogate or conventional neutralization assays. Once a cutoff is established, these relatively simple high-throughput antibody assays will provide a fast and cost-effective method of assessing levels of protection from SARS-CoV-2 infection. IMPORTANCE Neutralizing antibody titers are the best correlate of protection against SARS-CoV-2. However, current tests to measure plasma or serum neutralizing activity do not allow high-throughput screening at the population level. Serological tests could be an alternative if they are proved to be good predictors of plasma neutralizing activity. In this study, we analyzed the SARS-CoV-2 serological profiles of two cohorts of health care workers by applying Luminex and ELISA in-house serological assays. Correlations of both serological tests were assessed between them and with a flow cytometry assay to determine plasma surrogate-neutralizing activity. Both assays showed a high positive correlation between IgG levels to S antigens, especially RBD, and the levels of plasma surrogate-neutralizing activity. This result suggests IgG to RBD as a good correlate of plasma surrogate-neutralizing activity and indicates that serology of IgG to RBD could be used to assess levels of protection from SARS-CoV-2 infection.

Cerebral small vessel disease burden and cognitive and functional outcomes after stroke: A multicenter prospective cohort study.

INTRODUCTION: It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes. METHODS: In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular spaces) and explored associations with 6- and 12-month cognitive (battery of 15 neuropsychological tests) and functional (modified Rankin scale) outcomes. RESULTS: A global SVD score (range 0-4) was associated with cognitive impairment; worse performance in executive function, attention, language, and visuospatial ability; and worse functional outcome across a 12-month follow-up. Although the global SVD score did not improve prediction, individual SVD markers, assessed across their severity range, improved the calibration, discrimination, and reclassification of predictive models including demographic, clinical, and other imaging factors. DISCUSSION: SVD presence and severity are associated with worse cognitive and functional outcomes 12 months after stroke. Assessing SVD severity may aid prognostication for stroke patients. HIGHLIGHTS: In a multi-center cohort, we explored associations of small vessel disease (SVD) burden with stroke outcomes. SVD burden associates with post-stroke cognitive and functional outcomes. A currently used score of SVD burden does not improve the prediction of poor outcomes. Assessing the severity of SVD lesions adds predictive value beyond known predictors. To add predictive value in assessing SVD in stroke patients, SVD burden scores should integrate lesion severity.

Two-Year Follow-Up on Chemosensory Dysfunction and Adaptive Immune Response after Infection with SARS-CoV-2 in a Cohort of 44 Healthcare Workers.

Persistent chemosensory dysfunction (PCD) is a common symptom of long-COVID. Chemosensory dysfunction (CD) as well as SARS-CoV-2-specific antibody levels and CD8+ T-cell immunity were investigated in a cohort of 44 healthcare workers up to a median of 721 days after a positive PCR test. CD was assessed using questionnaires and psychophysical screening tests. After 721 days, 11 of 44 (25%) participants reported PCD, with five describing an impaired quality of life. One participant reported hyperosmia (increased sense of smell). The risk of PCD at 721 days was higher for participants reporting qualitative changes (parosmia (altered smell), dysgeusia (altered taste), or phantosmia (hallucination of smell)) during initial infection than in those with isolated quantitative losses during the first COVID-19 infection (62.5% vs. 7.1%). The main recovery rate occurred within the first 100 days and did not continue until follow-up at 2 years. No correlation was found between antibody levels and CD, but we observed a trend of a higher percentage of T-cell responders in participants with CD. In conclusion, a significant proportion of patients suffer from PCD and impaired quality of life 2 years after initial infection. Qualitative changes in smell or taste during COVID-19 pose a higher risk for PCD.

Histology of Cerebral Clots in Cryptogenic Stroke Varies According to the Presence of a Patent Foramen Ovale.

Although a pathophysiological impact remains difficult to prove in individual patient care, a patent foramen ovale (PFO) is currently considered of high relevance for secondary prophylaxis in selected patients with cryptogenic ischemic stroke. By quantification of histological clot composition, we aimed to enhance pathophysiological understanding of PFO attributable ischemic strokes. Retrospectively, we evaluated all cerebral clots retrieved by mechanical thrombectomy for acute ischemic stroke treatment between 2011 and 2021 at our comprehensive stroke care center. Inclusion criteria applied were cryptogenic stroke, age (≤60 years), and PFO status according to transesophageal echocardiography, resulting in a study population of 58 patients. Relative clot composition was calculated using orbit image analysis to define the ratio of main histologic components (fibrin/platelets (F/P), red blood cell count (RBC), leukocytes). Cryptogenic stroke patients with PFO (PFO+, n = 20) displayed a significantly higher percentage of RBC (0.57 ± 0.17; p = 0.002) and lower percentage of F/P (0.38 ± 0.15; p = 0.003) compared to patients without PFO (PFO-, n = 38) (RBC: 0.41 ± 0.21; F/P: 0.52 ± 0.20). In conclusion, histologic clot composition in cryptogenic stroke varies depending on the presence of a PFO. Our findings histologically support the concept that a PFO may be of pathophysiological relevance in cryptogenic ischemic stroke.

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial.

BACKGROUND: Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis. METHODS: International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up. RESULTS: Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88-1.53)/1.05 (95% CI, 0.78-1.42; P=0.629)/0.63 (95% CI, 0.43-0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21-0.99]; P=0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37-1.42]; P=0.343). CONCLUSIONS: Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01645306.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Complicated Carotid Artery Plaques and Risk of Recurrent Ischemic Stroke or TIA.

BACKGROUND: Complicated nonstenosing carotid artery plaques (CAPs) are an under-recognized cause of stroke. OBJECTIVES: The purpose of this study was to determine whether complicated CAP ipsilateral to acute ischemic anterior circulation stroke (icCAP) are associated with recurrent ischemic stroke or transient ischemic attack (TIA). METHODS: The CAPIAS (Carotid Plaque Imaging in Acute Stroke) multicenter study prospectively recruited patients with ischemic stroke restricted to the territory of a single carotid artery. Complicated (AHA-lesion type VI) CAP were defined by multisequence, contrast-enhanced carotid magnetic resonance imaging obtained within 10 days from stroke onset. Recurrent events were assessed after 3, 12, 24, and 36 months. The primary outcome was recurrent ischemic stroke or TIA. RESULTS: Among 196 patients enrolled, 104 patients had cryptogenic stroke and nonstenosing CAP. During a mean follow-up of 30 months, recurrent ischemic stroke or TIA occurred in 21 patients. Recurrent events were significantly more frequent in patients with icCAP than in patients without icCAP, both in the overall cohort (incidence rate [3-year interval]: 9.50 vs 3.61 per 100 patient-years; P = 0.025, log-rank test) and in patients with cryptogenic stroke (10.92 vs 1.82 per 100 patient-years; P = 0.003). The results were driven by ipsilateral events. A ruptured fibrous cap (HR: 4.91; 95% CI: 1.31-18.45; P = 0.018) and intraplaque hemorrhage (HR: 4.37; 95% CI: 1.20-15.97; P = 0.026) were associated with a significantly increased risk of recurrent events in patients with cryptogenic stroke. CONCLUSIONS: Complicated CAP ipsilateral to acute ischemic anterior circulation stroke are associated with an increased risk of recurrent ischemic stroke or TIA. Carotid plaque imaging identifies high-risk patients who might be suited for inclusion into future secondary prevention trials. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933).

Recruitment of highly cytotoxic CD8+ T cell receptors in mild SARS-CoV-2 infection.

T cell immunity is crucial for control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been studied widely on a quantitative level. However, the quality of responses, in particular of CD8+ T cells, has only been investigated marginally so far. Here, we isolate T cell receptor (TCR) repertoires specific for immunodominant SARS-CoV-2 epitopes restricted to common human Leukocyte antigen (HLA) class I molecules in convalescent individuals. SARS-CoV-2-specific CD8+ T cells are detected up to 12 months after infection. TCR repertoires are diverse, with heterogeneous functional avidity and cytotoxicity toward virus-infected cells, as demonstrated for TCR-engineered T cells. High TCR functionality correlates with gene signatures that, remarkably, could be retrieved for each epitope:HLA combination analyzed. Overall, our data demonstrate that polyclonal and highly functional CD8+ TCRs-classic features of protective immunity-are recruited upon mild SARS-CoV-2 infection, providing tools to assess the quality of and potentially restore functional CD8+ T cell immunity.

Long-Term Follow-up of Enhanced Holter-Electrocardiography Monitoring in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Prolonged electrocardiography (ECG)-monitoring in stroke patients improves the detection of paroxysmal atrial fibrillation (pAF). However, most randomized studies only had short follow-up. We aimed to provide 3-year follow-up data for AF detection and stroke recurrence risk. METHODS: We randomized 402 patients aged ≥60 years with acute ischemic strokes without AF to either enhanced and prolonged monitoring (EPM; 3×10-day Holter-ECG-monitoring) or standard-of-care (≥24 hours ECG-monitoring). The endpoint of the current analysis was AF within 36 months analyzed by intention to treat. Long-term follow-up was performed for 36 months. RESULTS: Two hundred and seventy-four patients (80%) participated in the extended follow-up (median duration of follow-up was 36 months [interquartile range, 12 to 36]). During the first 6 months, more AF was documented in the EPM arm compared to the control arm (13.5% vs. 5.1%; 95% confidence interval, 2.9% to 14.4%; P=0.004). During months 6 to 36, AF was less detected in the EPM intervention arm than in the control arm (2.0% vs. 7.3%; 95% confidence interval, 0.7% to 9.9%; P=0.028). Overall, the detection rate of AF within 36 months was numerically higher within the EPM group (15.0% vs. 11.1%, P=0.30). Numerically less patients in the EPM arm had recurrent ischemic strokes (5.5% vs. 9.1%, P=0.18), transient ischemic attacks (3.0% vs. 4.5%, P=0.44) or died (4.5% vs. 6.6%, P=0.37). CONCLUSIONS: Enhanced and prolonged ECG monitoring increased AF detection during the first six months, but there was significantly more clinical AF during months 6 to 36 observed in the usual-care arm. This suggests that EPM leads to an earlier detection of clinically relevant AF.

Phantosmia, Parosmia, and Dysgeusia Are Prolonged and Late-Onset Symptoms of COVID-19.

Deficiencies in smell and taste are common symptoms of COVID-19. Quantitative losses are well surveyed. This study focuses on qualitative changes such as phantosmia (hallucination of smell), parosmia (alteration of smell), and dysgeusia (alteration of taste) and possible connections with the adaptive immune system. Subjective experience of deficiency in taste and smell was assessed by two different questionnaires after a median of 100 and 244 days after first positive RT-PCR test. SARS-CoV-2-specific antibody levels were measured with the iFlash-SARS-CoV-2 assay. After 100 days a psychophysical screening test for olfactory and gustatory dysfunction was administered. 30 of 44 (68.2%) participants reported a chemosensory dysfunction (14 quantitative, 6 qualitative, 10 quantitative, and qualitative) during COVID-19, eleven (25.0%) participants (1 quantitative, 7 qualitative, 3 quantitative, and quantity) after 100 days, and 14 (31.8%) participants (1 quantitative, 10 qualitative, 3 quantitative and qualitative) after 244 days. Four (9.1%) participants, who were symptom-free after 100 days reported now recently arisen qualitative changes. Serological and T-cell analysis showed no correlation with impairment of taste and smell. In conclusion, qualitative changes can persist for several months and occur as late-onset symptoms months after full recovery from COVID-19-induced quantitative losses in taste and smell.

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Artery Stenosis: Design and Rationale of a Randomized Phase II Clinical Trial.

Patients with stroke or transient ischemic attacks (TIAs) and internal carotid artery stenosis harbor an increased risk of recurrent stroke especially within 2 weeks after the first event. In addition, the revascularization procedure itself (carotid endarterectomy [CEA] or carotid artery stenting [CAS]) is associated with both clinically apparent and silent brain infarctions, mainly caused by the embolic nature of the ruptured carotid plaque. The glycoprotein VI (GPVI) fusion protein Revacept is a highly specific antithrombotic drug without direct inhibition of systemic platelet function that might reduce periprocedural distal embolization from the vulnerable ruptured plaque located at the internal carotid artery. By shielding collagen at the site of vascular injury, Revacept inhibits plaque-mediated platelet adhesion and aggregation, while not directly affecting systemic hemostasis. In this phase II study, 158 patients with symptomatic carotid artery stenosis with recent TIA or stroke were randomized to receive a single dose of either Revacept (40 or 120 mg) or placebo. All patients were on standard secondary preventive therapy (statins and platelet inhibition) and underwent CEA, CAS, or best medical therapy according to current guidelines. The efficacy of Revacept was evaluated by exploratory assessment of new diffusion-weighted imaging lesions on magnetic resonance imaging after the revascularization procedure; a combination of cardiovascular events (ischemic and hemorrhagic stroke, TIA, myocardial infarction, or coronary intervention) and bleeding complications served to assess clinically critical patients' outcome and safety. This exploratory phase II randomized, double-blind clinical trial provides valuable insights on the safety, tolerability, and efficacy of Revacept in patients with symptomatic carotid artery stenosis.

Complicated Carotid Artery Plaques as a Cause of Cryptogenic Stroke.

BACKGROUND: The underlying etiology of ischemic stroke remains unknown in up to 30% of patients. OBJECTIVES: This study explored the causal role of complicated (American Heart Association-lesion type VI) nonstenosing carotid artery plaques (CAPs) in cryptogenic stroke (CS). METHODS: CAPIAS (Carotid Plaque Imaging in Acute Stroke) is an observational multicenter study that prospectively recruited patients aged older than 49 years with acute ischemic stroke that was restricted to the territory of a single carotid artery on brain magnetic resonance imaging (MRI) and unilateral or bilateral CAP (≥2 mm, NASCET [North American Symptomatic Carotid Endarterectomy Trial] <70%). CAP characteristics were determined qualitatively and quantitatively by high-resolution, contrast-enhanced carotid MRI at 3T using dedicated surface coils. The pre-specified study hypotheses were that that the prevalence of complicated CAP would be higher ipsilateral to the infarct than contralateral to the infarct in CS and higher in CS compared with patients with cardioembolic or small vessel stroke (CES/SVS) as a combined reference group. Patients with large artery stroke (LAS) and NASCET 50% to 69% stenosis served as an additional comparison group. RESULTS: Among 234 recruited patients, 196 had either CS (n = 104), CES/SVS (n = 79), or LAS (n = 19) and complete carotid MRI data. The prevalence of complicated CAP in patients with CS was significantly higher ipsilateral (31%) to the infarct compared with contralateral to the infarct (12%; p = 0.0005). Moreover, the prevalence of ipsilateral complicated CAP was significantly higher in CS (31%) compared with CES/SVS (15%; p = 0.02) and lower in CS compared with LAS (68%; p = 0.003). Lipid-rich and/or necrotic cores in ipsilateral CAP were significantly larger in CS compared with CES/SVS (p < 0.05). CONCLUSIONS: These findings substantiate the role of complicated nonstenosing CAP as an under-recognized cause of stroke. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933).

Thrombus NET content is associated with clinical outcome in stroke and myocardial infarction.

OBJECTIVE: To investigate whether immune cell composition and content of neutrophil extracellular traps (NETs) in relation to clinical outcome are different between acute ischemic stroke (AIS) and acute myocardial infarction (AMI), we performed histologic analysis and correlated results with clinical and procedural parameters. METHODS: We retrieved thrombi from patients with AIS (n = 71) and AMI (n = 72) during endovascular arterial recanalization and analyzed their immune cell composition and NET content by immunohistology. We then associated thrombus composition with procedural parameters and outcome in AIS and with cardiac function in patients with AMI. Furthermore, we compared AIS thrombi with AMI thrombi and differentiated Trial of Org 10172 in Acute Stroke Treatment classifications to address potential differences in thrombus pathogenesis. RESULTS: Amounts of leukocytes (p = 0.133) and neutrophils (p = 0.56) were similar between AIS and AMI thrombi. Monocytes (p = 0.0052), eosinophils (p < 0.0001), B cells (p < 0.0001), and T cells (p < 0.0001) were more abundant in stroke compared with AMI thrombi. NETs were present in 100% of patients with AIS and 20.8% of patients with AMI. Their abundance in thrombi was associated with poor outcome scores in patients with AIS and with reduced ejection fraction in patients with AMI. CONCLUSION: In our detailed histologic analysis of arterial thrombi, thrombus composition and especially abundance of leukocyte subsets differed between patients with AIS and AMI. The presence and amount of NETs were associated with patients' outcome after AIS and AMI, supporting a critical impact of NETs on thrombus stability in both conditions.

Prediction of Stroke Risk by Detection of Hemorrhage in Carotid Plaques: Meta-Analysis of Individual Patient Data.

OBJECTIVES: The goal of this study was to compare the risk of stroke between patients with carotid artery disease with and without the presence of intraplaque hemorrhage (IPH) on magnetic resonance imaging. BACKGROUND: IPH in carotid stenosis increases the risk of cerebrovascular events. Uncertainty remains whether risk of stroke alone is increased and whether stroke is predicted independently of known risk factors. METHODS: Data were pooled from 7 cohort studies including 560 patients with symptomatic carotid stenosis and 136 patients with asymptomatic carotid stenosis. Hazards of ipsilateral ischemic stroke (primary outcome) were compared between patients with and without IPH, adjusted for clinical risk factors. RESULTS: IPH was present in 51.6% of patients with symptomatic carotid stenosis and 29.4% of patients with asymptomatic carotid stenosis. During 1,121 observed person-years, 66 ipsilateral strokes occurred. Presence of IPH at baseline increased the risk of ipsilateral stroke both in symptomatic (hazard ratio [HR]: 10.2; 95% confidence interval [CI]: 4.6 to 22.5) and asymptomatic (HR: 7.9; 95% CI: 1.3 to 47.6) patients. Among patients with symptomatic carotid stenosis, annualized event rates of ipsilateral stroke in those with IPH versus those without IPH were 9.0% versus 0.7% (<50% stenosis), 18.1% versus 2.1% (50% to 69% stenosis), and 29.3% versus 1.5% (70% to 99% stenosis). Annualized event rates among patients with asymptomatic carotid stenosis were 5.4% in those with IPH versus 0.8% in those without IPH. Multivariate analysis identified IPH (HR: 11.0; 95% CI: 4.8 to 25.1) and severe degree of stenosis (HR: 3.3; 95% CI: 1.4 to 7.8) as independent predictors of ipsilateral stroke. CONCLUSIONS: IPH is common in patients with symptomatic and asymptomatic carotid stenosis and is a stronger predictor of stroke than any known clinical risk factors. Magnetic resonance imaging might help identify patients with carotid disease who would benefit from revascularization.

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium.

AIMS: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. METHODS AND RESULTS: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. CONCLUSION: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.